The detection of specified antigens (defined as a substance whose introduction into an animal stimulates the production of antibodies capable of reacting specifically therewith), haptens (a substance requiring additional accessory materials before its introduction into an animal stimulates the production of antibodies specific therefor), analytes and the like substances (hereinafter collectively referred to as antigens) in body fluids such as blood, sputum, urine, and the like has in recent years become of utmost importance in both the research and clinical environments. The detection of antigens, and antibodies can often be related to various disease states and consequently is of extreme usefulness in diagnosis as well as gaining basic understandings concerning the genesis of disease as well as monitoring the effectiveness and side effects of therapies therefor.
One organ for which immunoassays for disease conditions is constantly sought, is the kidney. Early efforts in this regard have typically focused on detecting various renal associated enzymes. For instance, Wellwood et al. described such a method in an article entitled "Urinary N-Acetyl-.beta.-D-Glucosaminidase Assay In Renal Transplant Recipients" (Transplantation 26: 396-400, 1978) wherein urinary NAG activity was measured in an attempt to assess renal related cellular injury. In particular, it was hoped that NAG would prove to be a valuable aid in the early diagnosis of renal transplant rejections. Unfortunately, other causes including oliguria, hypotension, chronic rejection, renal vein thrombosis, and gentamicin administration also resulted in altered NAG excretion levels thus greatly reducing the utility of any NAG related assay due to its nonspecificity.
Similar studies by Mondorf et al. ("Brush Border Enzymes and Drug Nephrotoxicity", Acute Renal Failure, Editor Solez and Whelton, Marcel Dekker, Inc., ISBN 0-8247-1904-2, 1984) attempted to correlate drug induced renal cell damage with excreted brush border enzymes such as alanine aminopeptidase (AAP) and the presence of cellular fragments. The assays were typically performed utilizing isotopically labeled, gel filtration purified high molecular weight kidney antigens. These studies, like those of Wellwood et al., obtained results which were difficult to correlate with specific renal diseases, in particular diseases or conditions affecting particular internal kidney structures. Jung et al. ("Influence of pH on the Activity of Enzymes in Urine at 37.degree. C.", Clinical Chemistry Vol. 28, 8: 1814, 1982), and Bastable (.beta..sub.2 -Microglobulin in Urine: Not Suitable for Assessing Renal Tubular Function", Clinical Chemistry Vol. 29, 5: 996-997, 1983) have indicated that questionable results may be due in large measure to the variable effects associated with urine pHs. The less than physiological pHs typical of urine deleteriously affects enzyme activity, often in a nonrepeatable manner.
Sachse et al. have described ("Development of a Radioimmunoassay for a High Molecular Mass Tubular Antigen in Urine-Its Application for Early Detection of Tubular Damage", Clinica Chimica Acta. 110: 91-104, 1981) the detection of enzymes and uncharacterized antigenic components of undisclosed high molecular mass and their relation to kidney cellular damage through inhibition binding experiments with isotopically labeled urinary antigens. A practical assay specific for particular renal cell type damage, however, was not disclosed; such being still another object of the present invention.
It is an object of the present invention to provide an assay suitable for the detection of specific renal associated diseases.
It is a related object of the present invention to provide assays capable of detecting proximal tubule damaging diseases.
It is yet another object of the present invention to provide a means for detecting renal associated diseases by assaying for shed normal, renal tissue associated antigens in body fluids.
It is yet another related object of the present invention to avoid reliance upon conventional renal enzyme detection schemes.
It is yet a further related object to provide means for monitoring drugs and particularly levels thereof which may be capable of inducing renal cellular damage.
Ueda et al., at Sloan-Kettering Cancer Center, described the isolation and reactivity of seventeen monoclonal antibodies derived from fusions with spleen cells of mice immunized with established culture lines of renal cancers ("Cell Surface Antigens of Human Renal Cancer Defined by Mouse Monoclonal Antibodies: Identification of Tissue-specific Kidney Glycoproteins", Proc. Natl. Acad. Sci., Vol. 78: 5122-5126, 1981). That work resulted in the description of nine cell surface antigenic systems including the most restricted antigens gp160, S.sub.25, and gp120r. The primary object of those studies was to identify cancer specific antigens, however, none of the mouse antibodies cited in that publication were successful in that regard.
It is a further related object of the present invention to build upon the work of Ueda et al. by identifying which of the Ueda antibodies may be used in the manner of the present invention to derive an assay meeting the desired and stated object.